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Intermittent fasting (IF) is a diet with salutary effects on cognitive aging, Alzheimer's disease (AD), and stroke. IF restricts a number of nutrient components, including glucose. 2-deoxyglucose (2-DG), a glucose analog, can be used to mimic glucose restriction. 2-DG induced transcription of the pro-plasticity factor, Bdnf , in the brain without ketosis. Accordingly, 2-DG enhanced memory in an AD model (5xFAD) and functional recovery in an ischemic stroke model. 2-DG increased Bdnf transcription via reduced N-linked glycosylation, consequent ER stress, and activity of ATF4 at an enhancer of the Bdnf gene, as well as other regulatory regions of plasticity/regeneration (e.g., Creb5 , Cdc42bpa , Ppp3cc , and Atf3) genes. These findings demonstrate an unrecognized role for N-linked glycosylation as an adaptive sensor to reduced glucose availability. They further demonstrate that ER stress induced by 2-DG can, in the absence of ketosis, lead to the transcription of genes involved in plasticity and cognitive resilience as well as proteostasis. [Display omitted] • 2-deoxyglucose (2-DG), a glucose-restriction mimetic, drives Bdnf transcription • 2-DG reduces disability after ischemic stroke and improves cognition in AD • 2-DG inhibits N-glycosylation to induce ER stress, ATF4, and Bdnf transcription • N-glycosylation senses low glucose to drive adaptation to stroke and AD Intermittent fasting (IF) is a nutritional paradigm that forestalls cognitive aging, stroke disability, and Alzheimer's progression. How glucose restriction, an aspect of IF, contributes to IF-induced benefits is unclear. Here, we used 2-deoxyglucose to elucidate how low glucose engages an evolutionarily conserved ER stress response pathway to stimulate brain plasticity and treat stroke and AD. [ABSTRACT FROM AUTHOR]

The ubiquitous volume-regulated anion channels (VRACs) facilitate cell volume control and contribute to many other physiological processes. Treatment with non-specific VRAC blockers or brain-specific deletion of the essential VRAC subunit LRRC8A is highly protective in rodent models of stroke. Here, we tested the widely accepted idea that the harmful effects of VRACs are mediated by release of the excitatory neurotransmitter glutamate. We produced conditional LRRC8A knockout either exclusively in astrocytes or in the majority of brain cells. Genetically modified mice were subjected to an experimental stroke (middle cerebral artery occlusion). The astrocytic LRRC8A knockout yielded no protection. Conversely, the brain-wide LRRC8A deletion strongly reduced cerebral infarction in both heterozygous (Het) and full KO mice. Yet, despite identical protection, Het mice had full swelling-activated glutamate release, whereas KO animals showed its virtual absence. These findings suggest that LRRC8A contributes to ischemic brain injury via a mechanism other than VRAC-mediated glutamate release., Competing Interests: One of the co-authors of this manuscript (R.S.) has pending patent applications covering the use of LRRC8 complex modulators for therapeutic purposes. Other authors declare no competing interests., (© 2023 The Author(s).)